The 'immunologic advantage' of HIV-exposed seronegative individuals

In 1989, a curious phenomenon was described: HIV specific T-cell responses to the viral envelope and core proteins could be detected in antibody-positive and antigen-negative sexual partners of known HIV-positive men [1]. Two other reports confirmed that initial observation on a total of six exposed seronegative (ESN) individuals, and the author raised the possibility that exposure to HIV that did not result in seroconversion and infection could be associated with the exclusive priming of T lymphocytes [2,3]. Analyses performed in different cohorts of individuals at high risk of HIV infection, including healthcare workers parenterally exposed to HIV and healthy newborns of HIV-infected mothers, revealed that HIV-specific CD4+ T helper cells, but not antibodies, were present in these persons [4,5]. These observations led to the hypothesis that viral exposure resulting in the exclusive priming of HIV-specific T cells could be associated with protection against the establishment of HIV infection [6]. This hypothesis was greatly strengthened by the independent observations that although the majority of commercial sex workers in Nairobi (the Pumwani cohort) became HIV-infected within a year, a sizable minority, subsequently estimated to be around 15% of the individuals tested, showed resistance to infection [7]; and that HIV-specific cytotoxic T lymphocytes (CTLs) could be isolated from healthy uninfected newborns of HIV-infected mothers [8]. The novel concept of 'resistance' to HIV infection in HIV-exposed individuals was proposed, and the search for immune correlates of such protection against HIV infection was initiated at that point. Subsequent pivotal reports showed that in HIV-exposed but uninfected individuals a particular genetic background, epitomized by the Δ32 deletion in the CCR5 receptor gene, can be detected [9], the production of soluble factors, including the CD8+ cell antiviral factor (CAF) and beta-chemokines, is increased [10-12], secretory HIV-specific IgA as well as T helper cells and CTLs can be observed in cervico-vaginal fluids and ejaculates [13,14], and natural killer (NK) cell activity is particularly potent [15]. Thus, 15 years after the first description of the detection of HIV-specific T helper cells in seronegative individuals, the 'immunologic advantage' possibly conferring resistance to HIV infection can be summarized as being correlated with the elicitation of systemic and mucosal cell-mediated immunity, presumably within favorable genetic and innate immunity settings. The suggested multiple components of this 'immunologic advantage' are summarized in Fig. 1 and will be discussed in detail within this review.